1. Field of Invention
The present invention relates to a method of controlling emesis caused by administration of non-platinum anti-cancer drugs to warm-blooded animals which utilizes certain N-(3-quinuclidinyl)benzamides and thiobenzamides; namely, the 2-alkoxy-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamides.
2. Information Disclosure Statement
Certain compounds useful in the present invention and pharmaceutical compositions thereof were disclosed in U.S. application for patent Ser. No. 597,275 filed Apr. 6, 1984, and a continuation U.S. application for patent Ser. No. 788,190 filed Oct. 15, 1985, as having gastric emptying and anti-emetic properties, especially anti-emetic properties against emesis caused by administration of platinum-containing anti-cancer drugs.
Imbert, T. et al. in French Pat. No. 2,529,548 disclose that certain compounds useful in the present invention have gastric emptying properties; however, they do not disclose any anti-emetic properties exhibited by said compounds.
Quinuclidine analogs of sulpiride were prepared and studied by Mikhlina, E. E. et al. as reported in Khim-Farmatsevt, Zh. 10, No. 11, 56-60 (1976); C.A. 86: 155489r exemplified by the compound: 5-aminosulfonyl-N-(1-azabicyclo [2.2.2]oct-3-yl)-2-methoxybenzamide. This compound and others in the series were reported by the authors not to have anti-emetic activity. The above named compound was reported in USSR Pat. No. SU-414-261 to have neuroleptic activity. The compounds of the present invention show anti-emetic activity without neuroleptic activity (blockade of d-amphetamine lethality in mice).
Syntheses of 4-amino-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamide and N-(1-azabicyclo[2.2.2]oct-3-yl)benzamide were reported by Mikhlina, E. E. et al. in Khim-Farmatsevt. Zh. 7, 20-24 (1974); C.A. 79: 146358a and the latter in Khim. Geterosikl. Soedin., Akad. Nauk. Latv. SSR 243-9 (1966); C.A. 65: 2220b. These compounds were reported to exhibit hypotensive, narcotic and ganglionic stimulation and blocking activities, properties not seen in the compounds of the present invention.
Synthesis of 4-amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-3-chloro-5-trifluoromethylbenzamid e was reported in Ger. Offen. No. 2,548,968; C.A. 87: 68001c and equivalently related U.S. Pat. No. 4,093,734 from 4-amino-3-chloro-5-trifluoromethylbenzoic acid chloride and 3-aminoquinuclidine. The compound is in a class among pyrrolidinyl and piperidinyl benzamides which are said to be useful as anxiolytics, anticonvulsives, antiemetics and antiulcerogenics. None of the compounds have orthoalkoxy substitution on benzamide as do the compounds of the present invention.
It is widely recognized that substituted benzamides are a class of drugs known to be effective in psychiatry [Sulpiride and Other Benzamides; International Workshop on Sulpiride and Other Benzamides, Florence, Feb. 17-18 (1978), Raven Press]. However, the 2-alkoxy-N-(1-azabicyclo[2.2.2]oct-3-yl)benazmides of this invention do not show neuropharmacological activity. This is in marked contrast to the compounds described in the prior art which show a range of pharmacological activities that include neuropharmacological effects.